Inhibition of human p53 basal transcription by down-regulation of protein kinase Cδ
Inhibition of human p53 basal transcription by down-regulation of protein kinase Cδ
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DOI：
10.1074/jbc.m306979200
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发表时间：
2004-03-12
影响因子：
4.8
通讯作者：
Bargonetti, J
中科院分区：
文献类型：
--
作者：
Abbas, T;White, D;Bargonetti, J
为了应对 DNA 损伤，信号转导途径被激活，导致 p53 蛋白水平增加，从而导致生长停滞或细胞凋亡。蛋白激酶 C (PKC) δ 被认为是一种肿瘤抑制因子，在小鼠皮肤和细胞培养模型中，它会被促进肿瘤的佛波酯下调。我们在此报告，促进肿瘤的佛波醇酯 12-O-tetradecanoylphorbol-13-acetate 通过下调 PKC delta 来防止 DNA 损伤诱导的 p53 上调。 p53 响应应激的调节最常见的方式是防止 p53 蛋白泛素化和降解。令人惊讶的是，通过抑制 PKC δ 来抑制 p53 表达是由抑制 p53 合成引起的，而不是增加 p53 蛋白的降解。抑制 PKC δ 可阻断人类 p53 基因的基础转录和人类 p53 启动子的转录起始。因此，PKC δ 的肿瘤抑制作用至少部分是通过激活 p53 转录介导的。
In response to DNA damage, signal transduction pathways are activated that result in the increase of p53 protein levels, leading to either growth arrest or apoptosis. Protein kinase C (PKC) delta has been implicated as a tumor suppressor that is down-regulated by tumor-promoting phorbol esters in both mouse skin and cell culture models. We report here that the tumor-promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate prevents DNA damage-induced up-regulation of p53 by down-regulating PKC delta. Regulation of p53 in response to stress most commonly occurs by preventing ubiquitination and degradation of the p53 protein. Surprisingly, suppression of p53 expression by inhibition of PKC delta was caused by the inhibition of p53 synthesis, not increased degradation of p53 protein. Inhibiting PKC delta blocked both basal transcription of the human p53 gene and initiation of transcription from the human p53 promoter. Therefore, the tumor-suppressing effects of PKC delta are mediated at least in part through activating p53 transcription.